There are a number of neurodegenerative polyglutamine diseases, for example Huntington's disease, spinocerebellar ataxia, and spinobulbar muscular atrophy (Kennedy's Disease), which are characterized by expanded genomic CAG sequences resulting in the synthesis and accumulation of polyglutamine tracts in brain proteins of unknown function (e.g., Huntingtin in Huntington's disease and ataxin in spinocerebellar ataxias) that are responsible for the neurologic problem. The CAG codon is translated into glutamine (Q). Proteins with expanded polyglutamine domains aggregate and aggregation is a pathologic hallmark of the polyglutamine repeat diseases (Hackam, A. S. et al. J Cell Biol 141, 1097-1105 (1998); Perez, M. K. et al. J Cell Biol 143, 1457-1470 (1998)). These polyglutamine length-dependent properties may arise from the ability of long polyglutamine domains to adopt unique three-dimensional conformations and serve to confer the disease proteins with a pathologic gain-of-function (Perutz, M. F. Trends Biochem Sci 24, 58-63 (1999); Lansbury, P. T. J. Proc Natl Acad Sci USA 96, 3342-3344 (1999)).
All diseases in the CAG repeat family show genetic anticipation, meaning the disease usually appears at an earlier age and increases in severity with each generation. Genetic anticipation is linked to increasing numbers of CAG repeats, which result from expansion of the unstable CAG sequence when reproductive cells divide to form eggs and sperm. In general, neurodegenerative disorders are progressive (i.e., their symptoms are not apparent until months or more commonly years after the disease has begun), and caused by an initial reduction of neuronal function, followed by a complete loss of function upon neuronal death.
Huntington's Disease (HD) is a devastating, degenerative brain disorder for which there is, at present, no effective treatment or cure. HD slowly diminishes the affected individual's ability to walk, think, talk and reason. Eventually, the person with HD becomes totally dependent upon others for his or her care. Huntington's Disease profoundly affects the lives of entire families: emotionally, socially and economically. Early symptoms of Huntington's Disease may affect cognitive ability or mobility and include depression, mood swings, forgetfulness, clumsiness, involuntary twitching and lack of coordination. As the disease progresses, concentration and short-term memory diminish and involuntary movements of the head, trunk and limbs increase. Walking, speaking and swallowing abilities deteriorate. Eventually the person is unable to care for him or herself. Death follows from complications, such as choking, infection or heart failure. HD typically begins in mid-life, between the ages of 30 and 45, though onset may occur as early as the age of 2. Children who develop the juvenile form of the disease rarely live to adulthood. HD affects males and females equally and crosses all ethnic and racial boundaries. Each child of a person with HD has a 50/50 chance of inheriting the fatal gene. HD is an autosomal dominant condition and thus everyone who carries the gene will develop the disease.
The Huntington's Disease (HD) gene was mapped to chromosome 4p16.3 in 1983 but eluded identification until 1993. When finally identified, the gene (IT15) was found to contain a CAG repeat within its 5′-end coding sequence (Cell 72:971-983). This CAG repeat is expanded in individuals with HD who may or may not be symptomatic. However, the presence of a CAG repeat expansion is found in virtually all symptomatic HD individuals (N. Engl. J. Med. 330:1401-1406).
Normal HD gene CAG repeats range from 10-29 repeats. Some normal individuals (<1%) have been found with intermediate HD gene CAG repeats of 30-35 repeats. Individuals affected with HD typically have at least one HD gene CAG repeat of 36 repeats or greater. It was also found that in a few rare instances (10 cases) individuals having repeats of 36-39 repeats had remained asymptomatic by standard clinical criteria at advanced age. In one exceptional case, a 95 year old patient had 39 repeats (Rubinsztein et. al., 1996; Am. J. Hum. Genet. 59:16-22). There is a tendency to an earlier age-of-onset of HD symptoms with increasing CAG repeat number. A review of 1,049 people (the majority of whom were symptomatic) has provided a determination of the likelihood of an age-of-onset for a given CAG repeat size for repeats between 39-50 repeats (Brinkman et al., 1997; Am. J. Hum. Genet. 60:1202-1210). The polyglutamine expansion results in the formation of insoluble, high molecular weight protein aggregates similar to those seen in Alzheimer's disease (Scherzinger et al., Cell 90:549-558 [1997]). Postmortem examination of the brains of patients suffering from Huntington's disease revealed that CAG repeat length positively correlates with the degree of DNA fragmentation within the afflicted striatum (Butterworth et al., Neurosci., 87:49-53 [1998]), indicating that neuronal degeneration observed in Huntington's disease may also occur through an apoptotic process.
Currently, physicians may prescribe a number of medications to help control emotional and movement problems associated with polyglutamine disorders caused by expanded genomic CAG nucleotides. Such medications include antipsychotic drugs, such as haloperidol, or other drugs, such as clonazepam, to alleviate choreic movements and also to help control hallucinations, delusions, and violent outbursts; fluoxetine, sertraline, nortriptyline, or other compounds may be prescribed for depression. Tranquilizers can help control anxiety and lithium may be prescribed to combat pathological excitement and severe mood swings. It is important to remember however, that while medicines may help keep these clinical symptoms under control, there is currently no treatment to stop or reverse the course of the disease.
Remacemide and Coenzyme Q10 have been tested for the treatment of HD but a large-scale clinical trial that tested the ability of these investigational drugs to slow the progression of Huntington's disease showed that neither drug resulted in any significant improvement for the patients. Remacemide blocks a neurotransmitter in the brain (the NMDA glutamate receptor) which has long been suspected of contributing to the death of brain cells in Huntington's disease. Coenzyme Q10 is a substance that occurs naturally in the body and plays a role in the function of mitochondria, the energy factories of human cells. It is also an anti-oxidant, meaning that it can neutralize potentially injurious oxygen-containing chemicals called free radicals, which may play a role in the nerve cell death that occurs in Huntington's disease. After one year of treatment, the disease seemed to progress more slowly in patients treated with Coenzyme Q10, however, the investigators concluded that overall the results were inconclusive as to whether there is real benefit from this drug (Neurology, Aug. 14, 2001; 57: 397).